Our experience indicating an important immunological role for the VEC in renal transplanation naturally led us to evaluate whether an autoantibody directed against VEC might play an initiating role in the pathogenesis of atherosclerosis. We have identified an autoantibody directed against antigens expressed on vascular endothelial cells (VEC) and peripheral blood monocytes in 37%(53/143) of non-selected patients with peripheral vascular disease at the Albany Medical College. The detected antibody is a highly cytotoxic, complement-fixing antibody directed against the endothelial cells lining the patient's own vessels. This autoantibody does not cross-react with autologous T or B lymphocytes. In age-matched controls an autoantibody directed against autologous VEC could be detected in only 9%(2/25) of normals, and was never detected in young controls. Our pilot study provides strong preliminary evidence for an autoantibody playing a role in the pathogenesis of atherosclerosis in a significant number of patients with proven vascular disease. If our preliminary observations are confirmed, namely that patients with vascular disease have an autoantibody directed against their own VEC, then this observation would have enormous implications in the prevention and treatment of vascular disease. Our approach is a new one but it is founded upon 9 years of experience on the VEC/monocyte antigen system. Our goal is to study a statistically significant number of vascular disease patients, incuding patients with coronary artery disease, for the presence and significance of this autoantibody. By correlating the development of this autoantibody to VEC with o ther historical and environmental factors, the possibility of preventive measures is enhanced. The discovery of this autoantibody in patients with vascular disease introduces the possibility of influencing this immune response, similar to that accomplished in transplantation biology and other autoimmune diseases, if a causal relationship is established by the proposed investigation.